Method of use of (imidazol-5-yl)methyl-2-quinolinone derivatives to inhibit smooth muscle cell proliferation

ABSTRACT

This invention comprises the use of compounds of formula (I)                    
     wherein the dotted line represents an optional bond; X is oxygen or sulfur; R 1  is hydrogen, C 1-12 alkyl, Ar 1 , Ar 2 C 1-6 alkyl, quinolinylC 1-6 alkyl, pyridylC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkyl, mono- or di(C 1-6 alkyl)aminoC 1-6 alkyl, aminoC 1-6 alkyl, or a radical of formula —Alk 1 —C(═O)—R 9 , —Alk 1 —S(O)—R 9  or —Alk 1 —S(O) 2 —R 9 ; R 2 , R 3  and R 16  each independently are hydrogen, hydroxy, halo, cyano, C 1-6 alkyl, C 1-6 alkyloxy, hydroxyC 1-6 alkyloxy, C 1-6 alkyloxy C 1-6 alkyloxy, aminoC 1-6 alkyloxy, mono- or di(C 1-6 alkyl)aminoC 1-6 alkyloxy, Ar 1 , Ar 2 C 1-6 alkyl, Ar 2 oxy, Ar 2 C 1-6 alkyloxy, hydroxycarbonyl, C 1-6 alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C 2-6 alkenyl; R 4  and R 5  each independently are hydrogen, halo, Ar 1 , C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkylthio, amino, hydroxycarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylS(O)C 1-6 alkyl or C 1-6 alkylS(O) 2 C 1-6 alkyl; R 6  and R 7  each independently are hydrogen, halo, cyano, C 1-6 alkyl, 4,4-dimethyl-oxazolyl, C 1-6 alkyloxy or Ar 2 oxy; R 8  is hydrogen, C 1-6 alkyl, cyano, hydroxycarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylcarbonylC 1-6 alkyl, cyanoC 1-6 alkyl, C 1-6 alkyloxycarbonylC 1-6 alkyl, carboxyC 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, mono- or di(C 1-6 alkyl)aminoC 1-6 alkyl, imidazolyl, haloC 1-6 alkyl, C 1-6 alkyloxyC 1-6 alkyl, aminocarbonylC 1-6 alkyl, or a radical of formula —O—R 10 , —S—R 10 , —N—R 11 R 12 ; R 17  is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkyloxycarbonyl, Ar 1 ; R 18  is hydrogen, C 1-6 alkyl, C 1-6 alkyloxy or halo; R 19  is hydrogen or C 1-6 alkyl; for the manufacture of a medicament to inhibit smooth muscle cell proliferation.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No. 09/996,147entitled “Method of use of (Imidazol-5-yl)Methyl-2-QuinolinoneDerivatives to Inhibit Smooth Muscle Cell Proliferation,” flied Nov. 28,2001, which is a divisional application of U.S. Ser. No. 09/445,009entitled “(Imidazol-5-yl)Methyl-2-Quinolinone Derivatives as Inhibitorsof Smooth Muscle Cell Proliferation,” filed on Nov. 30, 1999 now U.S.Pat. No. 6,365,600, which is a national stage application ofPCT/EP98/03182, filed on May 25, 1998, which application claims priorityfrom U.S. provisional application serial No. 06/047,376 filed Jun. 2,1997.

FIELD OF THE INVENTION

The present invention is concerned with a method of use of compounds offormula (I) for the inhibition of smooth muscle cell proliferation.

BACKGROUND OF THE INVENTION

Proliferation of smooth muscle cells of the arterial wall in response tolocal injury is an important aetiologic factor of vascular proliferativedisorders such as atherosclerosis and restenosis after angioplasty. Theincidence of restenosis after percutaneous transluminal coronaryangioplasty (PTCA) has been reported to be as high as 45% within threeto six months after PTCA treatment (Indolfi et al., Nature medicine, 1,541-545 (1995)). Hence, compounds that inhibit smooth muscle cellproliferation can be very useful to prevent or treat vascularproliferative disorders such as atherosclerosis and restenosis.

Heparin is a well known compound to inhibit proliferation of smoothmuscle cells after coronary angioplasty (Buchwald et al., J. Cardiovasc.Pharmacol., 28, 481-487 (1996)).

In our co-pending application PCT/EP96/04515, published on Jun. 19, 1997as WO-97/21701, the compounds of formula (I), their preparation andcompositions containing them are disclosed as farnesyl transferaseinhibitors useful for the treatment of ras dependent tumors.

DETAILED DESCRIPTION OF THE INVENTION

Unexpectedly, it has been found that the compounds of formula (I) can beused to inhibit smooth muscle cell proliferation. Consequently, thepresent invention relates to a method of use of compounds of formula (I)for treating vascular proliferative disorders in a warm-blooded animal.

The present invention relates to a method of use of compounds of formula(I)

the pharmaceutically acceptable acid or base addition salts and thestereochemically isomeric forms thereof, wherein

the dotted line represents an optional bond;

X is oxygen or sulfur;

R¹ is hydrogen, C₁₋₁₂alkyl, Ar¹, Ar²C₁₋₆alkyl, quinolinylC₁₋₆alkyl,pyridylC₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkyl, aminoC₁₋₆alkyl,

or a radical of formula —Alk¹—C(═O)—R⁹, —Alk¹—S(O)—R⁹ or —Alk¹—S(O)₂—R⁹,

wherein Alk¹ is C₁₋₆alkanediyl,

R⁹ is hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, amino, C₁₋₈alkylamino orC₁₋₈alkylamino substituted with C₁₋₆alkyloxycarbonyl;

R², R³ and R¹⁶ each independently are hydrogen, hydroxy, halo, cyano,C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy,aminoC₁₋₆alkyloxy, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, Ar¹,Ar²C₁₋₆alkyl, Ar²oxy, Ar²C₁₋₆alkyloxy, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C₂₋₆alkenyl,4,4-dimethyloxazolyl; or

when on adjacent positions R² and R³ taken together may form a bivalentradical of formula

—O—CH₂—O—  (a-1),

—O—CH₂—CH₂—O—  (a-2),

—O—CH═CH—  (a-3),

—O—CH₂—CH₂—  (a-4),

—O—CH₂—CH₂—CH₂—  (a-5), or

—CH═CH—CH═CH—  (a-6);

R⁴ and R⁵ each independently are hydrogen, halo, Ar¹, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio,amino, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylS(O)C₁₋₆alkyl orC₁₋₆alkylS(O)₂C₁₋₆alkyl;

R⁶ and R⁷ each independently are hydrogen, halo, cyano, C₁₋₆alkyl,C₁₋₆alkyloxy, Ar²oxy, trihalomethyl, C₁₋₆alkylthio, di(C₁₋₆alkyl)amino,or

when on adjacent positions R⁶ and R⁷ taken together may form a bivalentradical of formula

—O—CH₂—O—  (c-1), or

—CH═CH—CH═CH—  (c-2);

R⁸ is hydrogen, C₁₋₆alkyl, cyano, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonylC₁₋₆alkyl, cyanoC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, carboxyC₁₋₆alkyl, hydroxyC₁₋₆alkyl,aminoC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, imidazolyl,haloC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, or aradical of formula

—O—R¹⁰  (b-1),

—S—R¹⁰  (b-2),

—N—R¹¹R¹²  (b-3),

wherein R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹,Ar²C₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, or a radical or formula—Alk²—OR¹³ or —Alk²—NR¹⁴R¹⁵;

R¹¹ is hydrogen, C₁₋₁₂alkyl, Ar¹ or Ar²C₁₋₆alkyl;

R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylaminocarbonyl, Ar¹, Ar²C₁₋₆alkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl, anatural amino acid. Ar¹carbonyl, Ar²C₁₋₆alkylcarbonyl,aminocarbonylcarbonyl, C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy,C₁₋₆alkyloxy, aminocarbonyl, di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, amino,C₁₋₆alkylamino, C₁₋₆alkylcarbonylamino, or a radical or formula—Alk²—OR¹³ or —Alk²—NR¹⁴R¹⁵;

wherein Alk² is C₁₋₆alkanediyl;

R¹³ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkyl, Ar¹ orAr²C₁₋₆alkyl;

R¹⁴ is hydrogen, C₁₋₆alkyl, Ar¹ or Ar²C₁₋₆alkyl;

R¹⁵ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹ or Ar²C₁₋₆alkyl;

R¹⁷ is hydrogen, halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, Ar¹;

R¹⁸ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy or halo;

R¹⁹ is hydrogen or C₁₋₆alkyl;

Ar¹ is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy, amino,C₁₋₆alkyloxy or halo; and

Ar² is phenyl or phenyl substituted with C₁₋₆alkyl, hydroxy, amino,C₁₋₆alkyloxy or halo; for the inhibition of smooth muscle cellproliferation.

R⁴ or R⁵ may also be bound to one of the nitrogen atoms in the imidazolering. In that case the hydrogen on the nitrogen is replaced by R⁴ or R⁵and the meaning of R⁴ and R⁵ when bound to the nitrogen is limited tohydrogen, Ar¹, C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylS(O)C₁₋₆alkyl, C₁₋₆alkylS(O)₂C₁₋₆alkyl.

As used in the foregoing definitions and hereinafter halo definesfluoro, chloro, bromo and iodo; C₁₋₆alkyl defines straight and branchedchained saturated hydrocarbon radicals having from 1 to 6 carbon atomssuch as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl andthe like; C₁₋₈alkyl encompasses the straight and branched chainedsaturated hydrocarbon radicals as defined in C₁₋₆alkyl as well as thehigher homologues thereof containing 7 or 8 carbon atoms such as, forExample heptyl or octyl; C₁₋₁₂alkyl again encompasses C₁₋₈alkyl and thehigher homologues thereof containing 9 to 12 carbon atoms, such as, forexample, nonyl, decyl, undecyl, dodecyl; C₁₋₆alkyl again encompassesC₁₋₁₂alkyl and the higher homologues thereof containing 13 to 16 carbonatoms, such as, for example, tridecyl, tetradecyl, pentedecyl andhexadecyl; C₂₋₆alkenyl defines straight and branched chain hydrocarbonradicals containing one double bond and having from 2 to 6 carbon atomssuch as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl,3-pentenyl, 3-methyl-2-butenyl, and the like; C₁₋₆alkanediyl definesbivalent straight and branched chained saturated hydrocarbon radicalshaving from 1 to 6 carbon atoms, such as, for example, methylene,1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl,1,6-hexanediyl and the branched isomers thereof. The term “C(═O)” refersto a carbonyl group, “S(O)” refers to a sulfoxide and “S(O)₂” to asulfon. The term “natural amino acid” refers to a natural amino acidthat is bound via a covalent amide linkage formed by loss of a moleculeof water between the carboxyl group of the amino acid and the aminogroup of the remainder of the molecule. Examples of natural amino acidsare glycine, alanine, valine, leucine, isoleucine, methionine, proline,phenylanaline, tryptophan, serine, threonine, cysteine, tyrosine,asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine,histidine.

The pharmaceutically acceptable acid or base addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid and non-toxic base addition salt forms which the compounds offormula (I) are able to form. The compounds of formula (I) which havebasic properties can be converted in their pharmaceutically acceptableacid addition salts by treating said base form with an appropriate acid.Appropriate acids comprise, for example, inorganic acids such ashydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric;nitric; phosphoric and the like acids; or organic acids such as, forexample, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic,malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic,tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic,p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and thelike acids.

The compounds of formula (I) which have acidic properties may beconverted in their pharmaceutically acceptable base addition salts bytreating said acid form with a suitable organic or inorganic base.Appropriate base salt forms comprise, for example, the ammonium salts,the alkali and earth alkaline metal salts. e.g. the lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, andsalts with amino acids such as, for example, arginine, lysine and thelike.

The terms acid or base addition salt also comprise the hydrates and thesolvent addition forms which the compounds of formula (I) are able toform. Examples of such forms are e.g. hydrates, alcoholates and thelike.

The term stereochemically isomeric forms of compounds of formula (I), asused hereinbefore, defines all possible compounds made up of the sameatoms bonded by the same sequence of bonds but having differentthree-dimensional structures which are not interchangeable, which thecompounds of formula (I) may possess. Unless otherwise mentioned orindicated, the chemical designation of a compound encompasses themixture of all possible stereochemically isomeric forms which saidcompound may possess. Said mixture may contain all diastereomers and/orenantiomers of the basic molecular structure of said compound. Allstereochemically isomeric forms of the compounds of formula (I) both inpure form or in admixture with each other are intended to be embracedwithin the scope of the present invention.

Some of the compounds of formula (I) may also exist in their tautomericforms. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

Whenever used hereinafter, the term “compounds of formula (I)” is meantto include also the pharmaceutically acceptable acid or base additionsalts and all stereoisomeric forms.

Preferably the substituent R¹⁸ is situated on the 5 or 7 position of thequinolinone moiety and substituent R¹⁹ is situated on the 8 positionwhen R¹⁸ is on the 7-position.

Interesting compounds are these compounds of formula (I) wherein X isoxygen.

Also interesting compounds are these compounds of formula (I) whereinthe dotted line represents a bond, so as to form a double bond.

Another group of interesting compounds are those compounds of formula(I) wherein R¹ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,di(C₁₋₆alkyl)aminoC₁₋₆alkyl, or a radical of formula —Alk¹—C(═O)—R⁹,wherein Alk¹ is methylene and R⁹ is C₁₋₈alkylamino substituted withC₁₋₆alkyloxycarbonyl.

Still another group of interesting compounds are those compounds offormula (I) wherein R³ is hydrogen or halo: and R² is halo, C₁₋₆alkyl,C₂₋₆alkenyl, C₁₋₆alkyloxy, trihalomethoxy or hydroxyC₁₋₆alkyloxy.

A further group of interesting compounds are those compounds of formula(I) wherein R² and R³ are on adjacent positions and taken together toform a bivalent radical of formula (a-1), (a-2) or (a-3).

A still further group of interesting compounds are those compounds offormula (I) wherein R⁵ is hydrogen and R⁴ is hydrogen or C₁₋₆alkyl.

Yet another group of interesting compounds are those compounds offormula (I) wherein R⁷ is hydrogen; and R⁶ is C₁₋₆alkyl or halo,preferably chloro, especially 4-chloro.

A particular group of compounds are those compounds of formula (I)wherein R⁸ is hydrogen, hydroxy, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, imidazolyl, or a radicalof formula —NR¹¹R¹² wherein R¹¹ is hydrogen or C₁₋₁₂alkyl and R¹² ishydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxy,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, or a radical of formula —Alk²—OR¹³wherein R¹³ is hydrogen or C₁₋₆alkyl.

Prefered compounds are those compounds wherein R¹ is hydrogen,C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl, or aradical of formula —Alk¹—C(═O)—R⁹, wherein Alk¹ is methylene and R⁹ isC₁₋₈alkylamino substituted with C₁₋₆alkyloxycarbonyl; R² is halo,C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkyloxy, trihalomethoxy,hydroxyC₁₋₆alkyloxy or Ar¹; R³ is hydrogen; R⁴ is methyl bound to thenitrogen in 3-position of the imidazole; R⁵ is hydrogen; R⁶ is chloro;R⁷ is hydrogen; R⁸ is hydrogen, hydroxy, haloC₁₋₆alkyl,hydroxyC₁₋₆alkyl, cyanoC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl,imidazolyl, or a radical of formula —NR¹¹R¹² wherein R¹¹ is hydrogen orC₁₋₁₂alkyl and R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, or a radical of formula —Alk²—OR¹³wherein R¹³ is C₁₋₆alkyl; R¹⁷ is hydrogen and R¹⁸ is hydrogen.

Most preferred compounds are

4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone,

6-[amino(4-chlorophenyl)-1-methyl-1H-imidazol-5-ylmethyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone;

6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone;

6-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinonemonohydrochloride.monohydrate;

6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone,

6-amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-4-(3-propylphenyl)-2(1H)-quinolinone;a stereoisomeric form thereof or a pharmaceutically acceptable acid orbase addition salt; and

(+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone;or a pharmaceutically acceptable acid addition salt thereof.

The compounds of formula (I), wherein X is oxygen, said compounds beingrepresented by formula (I-a), may be prepared by hydrolysing anintermediate ether of formula (II), wherein R is C₁₋₆alkyl, according toart-known methods, such as stirring the intermediate of formula (II) inan aqueous acid solution. An appropriate acid is for instancehydrochloric acid. Subsequently the resulting quinolinone wherein R¹ ishydrogen may be transformed into a quinolinone, wherein R¹ has a meaningas defined hereinabove apart from hydrogen, by art-known N-alkylation.

The compounds of formula (I), wherein R⁸ is hydroxy, said compoundsbeing referred to as compounds of formula (I-b) may be prepared byreacting an intermediate ketone of formula (III) with a intermediate offormula (IV-a), wherein P is an optional protective group such as, forexample, a sulfonyl group, e.g. a dimethylamino sulfonyl group, whichcan be removed after the addition reaction. Said reaction requires thepresence of a suitable strong base, such as, for example, butyl lithiumin an appropriate solvent, such as, for example, tetrahydrofuran and thepresence an appropriate silanederivative, such as, for example,triethylchlorosilane. During the work-up procedure an intermediatesilane derivative is hydrolyzed. Other procedures with protective groupsanalogous to silanederivatives can also be applied.

Compounds of formula (I-b-1), being compounds of formula (I-b) whereinthe dotted line is a bond and R¹ is hydrogen, can be prepared byreacting an intermediate of formula (XXI) with an intermediate offormula (IV-a), as described hereinabove for the synthesis of compoundsof formula (I-b). The thus obtained intermediate of formula (XXII)undergoes ring opening of the isoxazole moiety by stirring it with anacid, such as, e.g. TiCl₃, in the presence of water. Subsequenttreatment of an intermediate of formula (XXIII) with a suitable reagentsuch as, e.g. R¹⁷CH₂COCl or R¹⁷CH₂COOC₂H₅, yields either directly acompound of formula (I-b-1) or an intermediate which can be converted toa compound of formula (I-b-1) by treatment with a base such as, e.g.potassium tert-butoxide.

Intermediates of formula (XXI) can conveniently be prepared by treatingan intermediate of formula (XVI), described hereinafter, under acidicconditions.

Compounds of formula (I) wherein R⁸ is a radical of formula —N—R¹¹R¹²,said compounds being represented by formula (I-g) may be prepared byreacting an intermediate of formula (XIII), wherein W is an appropriateleaving group such as, for example, halo, with a reagent of formula(XIV). Said reaction may be performed by stirring the reactants in anappropriate solvent such as, for example, tetrahydrofuran.

The compounds of formula (I) may also be prepared by convertingcompounds of formula (I) into other compounds of formula (I).

Compounds wherein the dotted line represents a bond can be convertedinto compounds wherein the dotted line does not represent a bond, byart-known hydrogenation methods. Vice versa, compounds wherein thedotted line does not represent a bond may be converted into compoundswherein the dotted line represents a bond by art-known oxidationreactions.

Compounds of formula (I) wherein R⁸ is hydroxy, said compounds beingrepresented by formula (I-b) may be converted into compounds of formula(I-c), wherein R^(8a) has the meaning of R¹⁰ except for hydrogen, byart-know O-alkylation or O-acylation reactions; such as, for instance,reacting the compound of formula (I-b) with an alkylating reagent suchas R^(8a)-W in appropriate conditions, such as, for example, a dipolaraprotic solvent, e.g. DMF, in the presence of a base, e.g. sodiumhydride. W is a suitable leaving group, such as, for example, halo or asulfonylgroup.

As an alternative to the above reaction procedure, compounds of formula(I-c) may also be prepared by reacting an intermediate of formula (I-b)with a reagent of formula R^(8a)—OH in acidic medium.

Compounds of formula (I-b) may also be converted into compounds offormula (I-g), wherein R¹¹ is hydrogen and R¹² is C₁₋₁₆alkylcarbonyl, byreacting compounds of formula (I-b) in acidic medium, such as sulfuricacid, with C₁₋₁₆alkyl-CN in a Ritter type reaction. Further, compoundsof formula (I-b) may also be converted into compounds of formula (I-g),wherein R¹¹ and R¹² are hydrogen, by reacting compounds (I-b) withammonium acetate and subsequent treatment with NH₃ (aq.).

Compounds of formula (I-b) may also be converted into compounds offormula (I-d), wherein R⁸ is hydrogen, by submitting the compounds offormula (I-b) to appropriate reducing conditions, such as, stirring intrifluoroacetic acid in the presence of an appropriate reducing agent,such as sodium borohydride or alternatively stirring the compounds offormula (I-b) in acetic acid in the presence of formamide. Furthermore,compounds of formula (I-d) wherein R⁸ is hydrogen may be converted intocompounds of formula (I-e) wherein R^(8b) is C₁₋₆alkyl by reactingcompounds of formula (I-d) with a reagent of formula (V) in anappropriate solvent, such as, for instance, diglyme in the presence of abase such as, for example, potassium butoxide.

A compound of formula (I-f), defined as a compound of formula (I)wherein X is sulfur may be prepared by reacting the correspondingcompound of formula (I-a), with a reagent like phosphorus pentasulfideor Lawesson's reagent in a suitable solvent such as, for example,pyridine.

Compounds of formula of formula (I), wherein R¹ is hydrogen and X isoxygen, said compounds being defined as compounds of formula (I-a-1) maybe prepared by reacting a nitrone of formula (VI) with the anhydride ofa carboxylic acid, such as, for example, acetic anhydride, thus formingthe corresponding ester on the 2 position of the quinoline moiety. Saidquinoline ester can be hydrolyzed in situ to the correspondingquinolinone using a base such as, for example, potassium carbonate.

Alternatively, compounds of formula (I-a-1) can be prepared by reactinga nitrone of formula (VI) with a sulfonyl containing electrophilicreagent such as, for example, p-toluenesulfonylchloride in the presenceof a base such as, for example, aqueous potassium carbonate. Thereaction initially involves the formation of a 2-hydroxy-quinolinederivative which is subsequently tautomerized to the desired quinolinonederivative. The application of art-known conditions of phase transfercatalysis may, enhance the rate of the reaction.

Compounds of formula (I-a-1) may also be prepared by an intramolecularphotochemical rearrangement of compounds of formula (VI). Saidrearrangement can be carried out by dissolving the reagents in areaction-inert solvent and irradiating at a wavelength of 366 nm. It isadvantageous to use degassed solutions and to conduct the reaction underan inert atmosphere such as, for example, oxygen free argon or nitrogengas, in order to minimize undesired side reactions or reduction ofquantum yield.

The compounds of formula (I) may also be converted into each other viaart-known reactions or functional group transformations. A number ofsuch transformations are already described hereinabove. Other examplesare hydrolysis of carboxylic esters to the corresponding carboxylic acidor alcohol; hydrolysis of amides to the corresponding carboxylic acidsor amines; hydrolysis of nitrites to the corresponding amides; aminogroups on imidazole or phenyl may be replaced by a hydrogen by art-knowndiazotation reactions and subsequent replacement of the diazo-group byhydrogen; alcohols may be converted into esters and ethers; primaryamines may be converted into secondary or tertiary amines; double bondsmay be hydrogenated to the corresponding single bond.

Intermediates of formula (III) may be prepared by reacting a quinolinonederivative of formula (VIII) with an intermediate of formula (IX) or afunctional derivative thereof under appropriate conditions, such as, forexample, a strong acid, e.g. polyphosphoric acid in an appropriatesolvent. The intermediate of formula (VIII) may be formed by cyclizationof an intermediate of formula (VII) by stirring in the presence of astrong acid, e.g. polyphosphoric acid. Optionally said cyclizationreaction may be followed by an oxidation step, which can be performed bystirring the intermediate formed after cyclization in an appropriatesolvent, such as, for example, a halogenated aromatic solvent, e.g.bromobenzene, in the presence of a oxidizing agent, e.g. bromine oriodine. At this stage it may also be appropriate to change the R¹substituent by art-known functional group transformation reaction.

Intermediates of formula (III-a-1), being intermediates of formula (III)wherein the dotted line is a bond, R¹ and R¹⁷ are hydrogen and X isoxygen, can be prepared starting from an intermediate of formula (XVII),which is conveniently prepared by protecting the corresponding ketone.Said intermediate of formula (XVII) is stirred with an intermediate offormula (XVIII) in the presence of a base such as sodium hydroxide, inan appropriate solvent, such as an alcohol, e.g. methanol. The thusobtained intermediate of formula (XVI) undergoes hydrolysis of the ketaland ring opening of the isoxazole moiety by stirring the intermediate offormula (XVI) with an acid, such as for example, TiCl₃, in the presenceof water. Subsequently acetic anhydride is used to prepare anintermediate of formula (XV), which undergoes ring closure in thepresence of a base such as, for example, potassium tert-butoxide.

Intermediates of formula (III-a-1) can easily be converted tointermediates of formula (III-a), defined as intermediates of formula(III) wherein the dotted line represents a bond, X is oxygen, R¹⁷ ishydrogen and R¹ is other than hydrogen, using art-known N-alkylationprocedures.

An alternative way to prepare intermediates of formula (III-a-1),wherein X is oxygen and R¹ is hydrogen, starts from an intermediate offormula (XVI), which is conveniently converted to intermediates offormula (XIX) using catalytic hydrogenation conditions, e.g. by usinghydrogen gas and palladium on carbon in a reaction-inert solvent suchas, e.g. tetrahydrofuran. Intermediates of formula (XIX) are convertedto intermediates of formula (XX) by submitting intermediates (XIX) to anacetylation reaction, e.g. by treatment with the anhydride of acarboxylic acid, e.g. acetic anhydride in a reaction-inert solvent, e.g.toluene, and subsequent treatment with a base such as, e.g. potassiumtert-butoxide in a reaction-inert solvent, e.g. 1,2-dimethoxyethane.Intermediates of formula (III-a-1) can be obtained by treatingintermediates of formula (XX) in acidic conditions.

Intermediates of formula (II) may be prepared by reacting anintermediate of formula (X), wherein W is an appropriate leaving group,such as, for example, halo, with an intermediate ketone of formula (XI).This reaction is performed by converting the intermediate of formula (X)into a organometallic compound, by stirring it with a strong base suchas butyl lithium and subsequently adding the intermediate ketone offormula (XI). Although this reaction gives at first instance a hydroxyderivative (i.e. R⁸ is hydroxy), said hydroxy derivative can beconverted into other intermediates wherein R⁸ has another definition byperforming art-known (functional group) transformations.

The intermediate nitrones of formula (VI) may be prepared by N-oxidizingquinoline derivatives of formula (XII) with an appropriate oxidizingagent such as, for example, m-chloro-peroxybenzoic acid or H₂O₂ in anappropriate solvent such as, for example, dichloromethane.

Said N-oxidation may also be carried out on a precursor of a quinolineof formula (XII).

The intermediates of formula (XII) are supposed to be metabolized invivo into compounds of formula (I) via intermediates of formula (VI).Hence, intermediates of formula (XII) and (VI) may act as prodrugs ofcompounds of formula (I).

The compounds of formula (I) and some of the intermediates have at leastone stereogenic center in their structure. This stereogenic center maybe present in a R or a S configuration.

The compounds of formula (I) as prepared in the hereinabove describedprocesses are generally racemic mixtures of enantiomers which can beseparated from one another following art-known resolution procedures.The racemic compounds of formula (I) may be converted into thecorresponding diastereomeric salt forms by reaction with a suitablechiral acid. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

This invention provides a method of use of compounds of formula (I) toinhibit the proliferation of smooth muscle cells, as illustrated bypharmacological Example C. 1.

Hence, the compounds of formula (I) can be used for the manufacture of amedicament for the inhibition of smooth muscle cell proliferation andconsequently the use for the manufacture of a medicament for thetreatment of vascular proliferative disorders such as atherosclerosisand restenosis is also provided.

It has been proposed in literature that the mechanism behind smoothmuscle cell proliferation involves the loss of normal regulation ofcellular growth, a process wherein ras proteins plays a significantrole. Accordingly, it has been suggested that compounds having farnesyltransferase inhibiting properties, can be useful to prevent smoothmuscle cell proliferation after vascular injury (Indolfi et al., Naturemedicine, 1, 541-545 (1995) and Irani et al., Biochemical aidbiophysical research Commmunications, 202, 1252-1258, (1994)).

Atherosclerosis is a disorder characterized by the deposition of fattysubstances in and fibrosis of the inner layer of the arteries.

Restenosis is the narrowing of tubular passageways of a subject afterthe tubular walls have been traumatized. This can be caused byuncontrolled cellular proliferation of neointimal tissue which often isa complication due to the use of revascularization techniques such as,e.g. saphenous vein bypass grafting, endarterectomy, percutaneoustransluminal coronary angioplasty (PTCA) and the like. Restenosis refersto a worsening or recurrence of lumenal stenosis in an artery which ischaracterized by a hyperplasia of cells of the arterial wall. In thisrespect, restenosis differs notably from an occlusion of the artery byan arterial atherosclerotic plaque or occlusion by thrombus.

Restenosis is not restricted or limited to the coronary arteries. It canalso occur in for Example peripheral vascular systems.

Angioplasty is a technique whereby an artery clogged by anatherosclerotic plaque and/or thrombus is mechanically cleared. Such aclogged or blocked artery prevents adequate blood flow. Angioplastyprocedures are much less invasive and much less traumatic thanconventional alternatives such as coronary bypass surgery and havegained widespread acceptance as a means of obtaining dilation orclearance of arteries. In conventional angioplasty procedures, a smallballoon-tipped catheter is introduced into an artery, often using aguide wire or a catheter tube in which a collapsed balloon may bepositioned at one more points of arterial stenosis, i.e. narrowing. Oncepositioned within the blockage, the balloon is inflated, therebystretching and/or fracturing the blockage and enlarging the lumen(opening) of the artery. After the balloon is deflated and removed fromthe artery, the artery's internal diameter is generally larger,resulting in restoration of blood flow. These balloon and catheterassemblies are often referred to as coronary balloon dilation catheters.However, said angioplasty procedures involve risk of both local andsystemic thromboembolic effects, tearing of an arterial wall andrestenosis.

Restenosis after balloon angioplasty is also referred to as‘percutaneous transluminal coronary angioplasty restenosis’ and ischaracterized by the return of blockage in the artery due to neointimalformation of a layer of smooth muscle cells in the intima after ballooninjury.

Accordingly, the present invention provides a method of treatingvascular proliferative disorders in a warm-blooded animal, such asatherosclerosis or restenosis, which comprises administering to saidwarm-blooded animal a prophylactically or therapeutically effectiveamount of a compound of formula (I).

The present invention provides further a method of inhibiting smoothmuscle cell proliferation in a warm-blooded animal which comprisesadministering to said warm-blooded animal a prophylactically ortherapeutically effective amount of a compound of formula (I).

Balloon angioplasty can be followed by a mechanical/surgical procedureknown as intravascular stenting, a procedure in which an expandablemetallic sleeve, or scaffold, i.e. a stent, is placed within the arteryafter angioplasty. However, after the insertion of the stent a disorderknown as ‘coronary artery stent restenosis’ can occur whereby theblockage in the artery returns due to neointimal formation of a layer ofsmooth muscle cells in the intima. Therefore, it may be advantageous tocover or coat said stent with a coating material which comprises acompounds of formula (I) in order to inhibit smooth muscle cellproliferation. Hence, in an aspect, this invention also provides stentscovered or coated with a coating material which comprises an amount of acompound of formula (I) effective in preventing, treating or reducingsmooth muscle cell proliferation. Commercially available stents are e.g.balloon expandable stents such as, e.g. Palmaz-Schatz™ stent, Strecker™stent and Gianturco-Roubin™ stent, and self expandable stents such as,e.g. Gianturco™ expandable wire stent and Wallstent™, other stents arePalmaz-Schatz Crown™, Cross-Flex™, ACS Multi-Link™, Nir™, Micro StentII™ and Wiktor™.

In a way, the invention also relates to catheters, or other transluminaldevices coated or covered with a coating material which comprises anamount of a compound of formula (I) effective in preventing, treating orreducing smooth muscle cell proliferation.

The metallic surface of a stent can be coated in a number of ways. Thesurface can be prepared by a two-step procedure including covalentlylinking an organosilane having amine reactive sites, with the surface ofthe metallic member, typically through a metal oxide thereof. Also, anorganosilane having a vinyl functionality pendant from the surface canbe used. Thereafter, a biocompatible coating material can be covalentlylinked to the organosilane coating.

The coating layer comprising an amount of a compound of formula (I) mayalso be applied as a mixture of a polymeric precursor and a compound offormula (I) which is finely divided or dissolved in a polymer solvent orvehicle which is thereafter cured in situ.

The coating may be applied by dipping or spraying using evaporativesolvent materials of relatively high vapor pressure to produce thedesired viscosity and coating thickness. The coating further is onewhich adheringly conforms to the surface of the filaments of the openstructure of the stent so that the open lattice nature of the structureof the braid or other pattern is preserved in the coated device.

The major constituent of the stent coating should have elastomericproperties. The stent coating is preferably a suitable hydrophobicbiostable elastomeric material which does not degrade and whichminimizes tissue rejection and tissue inflammation and one which willundergo encapsulation by tissue adjacent the stent implantation site.Polymers suitable for such coatings include silicones (e.g.polysiloxanes and substituted polysiloxanes), polyurethanes,thermoplastic elastomers in general, ethylene vinyl acetate copolymers,polyolefin elastomers, and EPDM rubbers.

The loading of the stent coating with the compound of formula (I) mayvary. The desired release rate profile can be tailored by varying thecoating thickness, the radial distribution, the mixing method, theamount of said compound of formula (I), and the crosslink density of thepolymeric material.

Methods for coating stents are described in, e.g. WO-96/32907, U.S. Pat.No. 5,607,475, U.S. Pat. No. 5,356,433, U.S. Pat. No. 5,213,898, U.S.Pat. No. 5,049403, U.S. Pat. No. 4,807,784 and U.S. Pat. No. 4,565,740.

Stents are made of a biocompatible material such as, e.g. stainlesssteel, tantalum, titanium, nitinol, gold, platinum, inconel, iridium,silver, tungsten, or another biocompatible metal, or alloys of any ofthese. Stainless steel and tantalum are particularly useful. Said stentcan be covered by one or more layers of a biocompatible coating materialsuch as, e.g. carbon, carbon fiber, cellulose acetate, cellulosenitrate, silicone, parylene, parylene derivatives, polyethyleneteraphthalate, polyurethane, polyamide, polyester, polyorthoester,polyanhydride, polyether sulfone, polycarbonate, polypropylene, highmolecular weight polyethylene, polytetrafluoroethylene, or anotherbiocompatible material, or mixture or copolymers of these. Parylene isboth a generic name for a known group of polymers based on p-xylene andmade by vapor phase polymerization, and a name for the unsubstituted oneof such polymers. Said one or more layers of biocompatible materialcomprise a compound of formula (I) of the present invention andadvantageously provide a controlled release of said compound of formula(I) effective in preventing, treating or reducing smooth muscle cellproliferation. Said one or more layers of biocompatible material canfurther comprise bioactive materials such as, e.g. heparin or anotherthrombin inhibitor, hirudin, hirulog, argatroban,D-phenylalanyl-L-poly-L-arginyl chloromethyl ketone, or anotherantithrombogenic agent, or mixtures thereof; urokinase, streptokinase, atissue plasminogen activator, or another thrombolytic agent, or mixturesthereof; a fibrinolytic agent: a vasospasm inhibitor; a calcium channelblocker, a nitrate, nitric oxide, a nitric oxide promoter or anothervasodilator; an antimicrobial agent or antibiotic; aspirin, ticlopdine,a glycoprotein IIb/IIIa inhibitor or another inhibitor of surfaceglycoprotein receptors, or another antiplatelet agent; colchicine oranother antimitotic, or another microtubule inhibitor; a retinoid oranother antisecretory agent; cytochalasin or another actin inhibitor;deoxyribonucleic acid, an antisense nucleotide or another agent formolecular genetic intervention; methotrexate or another antimetaboliteor antiproliferative agent; an anticancer chemotherapeutic agent;dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate oranother dexamethasone derivative, or another anti-inflammatory steroidor non-steroidal antiinflammatory agent: cyclosporin or anotherimmunosuppressive agent; trapidal (a PDGF antagonist), angiopeptin (agrowth hormone antagonist), an anti-growth factor antibody, or anothergrowth factor antagonist; dopamine, bromocriptine mesylate, pergolidemesylate or another dopamine agonist: captopril, enalapril or anotherangiotensin converting enzyme (ACE) inhibitor; ascorbic acid,alphatocopherol, superoxide dismutase, deferoxamine, a 21-aminosteroid(lasaroid) or another free radical scavenger; or a mixture of any ofthese.

Hence, the present invention further provides a method of treatingvascular proliferative disorders in a warm-blooded animal, such aspercutaneous transluminal coronary angioplasty restenosis or coronaryartery stent restenosis, which comprises administering to saidwarm-blooded animal a prophylactically or therapeutically effectiveamount of a compound of formula (I).

In particular said warm-blooded animal is a mammal or more specificallya human.

As is known to those skilled in the art, a prophylactically ortherapeutically effective amount varies with the type of therapeuticagent. It is known to those skilled in the art how to determine aprophylactically or therapeutically effective amount of a suitabletherapeutic agent.

In view of their useful pharmacological properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes. To prepare the pharmaceutical compositions ofthis invention, an effective amount of a particular compound, in base oracid addition salt form, as the active ingredient is combined inintimate admixture with a pharmaceutically acceptable carrier, whichcarrier may take a wide variety of forms depending on the form ofpreparation desired for administration. These pharmaceuticalcompositions are desirably in unitary dosage form suitable, preferably,for administration orally, rectally, percutaneously, or by parenteralinjection. For example, in preparing the compositions in oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols and the like in the case oforal liquid preparations such as suspensions, syrups, elixirs andsolutions; or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, to aid solubility for example, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. In the compositions suitable for percutaneous administration,the carrier optionally comprises a penetration enhancing agent and/or asuitable wetting agent, optionally combined with suitable additives ofany nature in minor proportions, which additives do not cause asignificant deleterious effect to the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment. It is especially advantageous to formulate theaforementioned pharmaceutical compositions in dosage unit form for easeof administration and uniformity of dosage. Dosage unit form as used inthe specification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

Those skilled in the art could easily determine the effective amountfrom the test results presented hereinafter. In general it iscontemplated that an effective amount would be from 0.0001 mg/kg to 100mg/kg body weight, and in particular from 0.001 mg/kg to 10 mg/kg bodyweight. It may be appropriate to administer the required dose as two,three, four or more sub-doses at appropriate intervals throughout theday. Said sub-doses may be formulated as unit dosage forms, for example,containing 0.01 to 500 mg, and in particular 0.1 mg to 200 mg of activeingredient per unit dosage form.

Experimental Part

Hereinafter “THF” means tetrahydrofuran, “DIPE” means diusopropylether,“DCM” means dichloromethane, “DMF” means N,N-dimethylformamide and “ACN”means acetonitrile. Of some compounds of formula (I) the absolutestereochemical configuration was not experimentally determined. In thosecases the stereochemically isomeric form which was first isolated isdesignated as “A” and the second as “B”, without further reference tothe actual stereochemical configuration.

A. Preparation of the Intermediates

EXAMPLE A.1

1a) N-Phenyl-3-(3-chlorophenyl)-2-propenamide (58.6 g) andpolyphosphoric acid (580 g) were stirred at 100° C. overnight. Theproduct was used without further purification, yielding quant.(±)-4-(3-chlorophenyl)-3,4-dihydro-2(1H)-quinolinone (interm. 1-a).

1b) Intermnediate (1-a) (58.6 g), 4-chlorobenzoic acid (71.2 g) andpolyphosphoric acid (580 g) were stirred at 140° C. for 48 hours. Themixture was poured into ice water and filtered off. The precipitate waswashed with water, then with a diluted NH₄OH solution and taken up inDCM. The organic layer was dried, filtered off and evaporated. Theresidue was purified by column chromatography over silica gel(eluent:CH₂Cl₂/CH₃OH/NH₄OH 99/1/0.1). The pure fractions were collectedand evaporated, and recrystallized from CH₂Cl₂/CH₃OH/DIPE, yielding 2.2g of(±)-6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-3,4-dihydro-2(1H)-quinolinone(interm. 1-b, mp. 194.8° C.).

1c) Bromine (3.4 ml) in bromobenzene (80 ml) was added dropwise at roomtemperature to a solution of intermediate (1-b) (26 g) in bromobenzene(250 ml) and the mixture was stirred at 160° C. overnight. The mixturewas cooled to room temperature and basified with NH₄OH. The mixture wasevaporated, the residue was taken up in ACN and filtered off. Theprecipitate was washed with water and air dried, yielding 24 g (92.7%)of product. A sample was recrystallized from CH₂Cl₂/CH₃OH/DIPE, yielding2.8 g of 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-2(1H)-quinolinone; mp.234.8° C. (interm. 1-c).

1d) Iodomethane (6.2 ml) was added to a mixture of intermediate (1-c)(20 g) and benzyltriethylammonium chloride (5.7 g) in tetrahydrofuran(200 ml) and sodium hydroxide (10N) (200 ml) and the mixture was stirredat room temperature overnight. ethyl acetate was added and the mixturewas decanted. The organic layer was washed with water, dried, filteredoff and evaporated till dryness. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH99.75/0.25/0.1). The pure fractions were collected and evaporated,yielding 12.3 g (75%) of6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone; mp.154.7° C. (interm. 1-d).

In a similar way, but starting from intermediate (1-b),(±)-6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-3,4-dihydro-1-methyl-2(1H)-quinolinone(interm 1-e) was prepared.

EXAMPLE A.2

Butyllithium in hexane (1.6 M) (12.75 ml) was added dropwise at −20° C.under N₂ to a solution of 6-bromo-4-(3-chlorophenyl)-2-methoxyquinoline(6.7 g) in THF (60 ml) and the mixture was stirred at −20° C. for 30minutes. A solution of(1-butyl-1H-imidazol-5-yl)(4-chlorophenyl)methanone (3.35 g) intetrahydrofuran (30 ml) was added at −20° C. under N₂ and the mixturewas stirred at room temperature for one night. Water was added and themixture was extracted with ethyl acetate. The organic layer was dried,filtered off and evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.1).The pure fractions were collected and evaporated, yielding 2.5 g (total48%) of(±)-α-(1-butyl-1H-imidazol-5-yl)-4-(3-chlorophenyl)-a-(4-chlorophenyl)-2-methoxy-6-quinoline-methanol(interm. 2).

EXAMPLE A.3

3a) Butyllithium (30.1 ml) was added slowly at −78° C. to a solution ofN,N-dimethyl-1H-imidazol-1-sulfonamide (8,4 g) in tetrahydrofuran (150ml) and the mixture was stirred at −78° C. for 15 minutes.Chlorotriethylsilane (8.1 ml) was added and the mixture was stirred tillthe temperature reached 20° C. The mixture was cooled till −78° C.,butyllithium (30.1 ml) was added, the mixture was stirred at −78° C. for1 hour and allowed to reach −15° C. The mixture was cooled again till−78° C., a solution of6-(4-chlorobenzoyl)-1-methyl-4-phenyl-2(1H)-quinolinone (15 g) intetrahydrofuran (30 ml) was added and the mixture was stirred till thetemperature reached 20° C. The mixture was hydrolized and extracted withethyl acetate. The organic layer was dried, filtered off and evaporatedtill dryness. The product was used without further purification,yielding 26 g (100%) of(±)-4-[(4-chlorophenyl)(1,2-dihydro-1-methyl-2-oxo-4-phenyl-6-quinolinyl)hydroxymethyl]-N,N-dimethyl-2-(triethylsilyl)-1H-imidazole-1-sulfonamide(inter-m. 3-a).

A mixture of intermediate (3-a) (26 g) in sulfuric acid (2.5 ml) andwater (250 ml) was stirred and heated at 110° C. for 2 hours. Themixture was poured into ice, basified with NH₄OH and extracted with DCM.The organic layer was dried, filtered off and evaporated till dryness.The residue was purified by column chromatography over silica gel(eluent: CH₂Cl₂/CH₃OH/NH₄OH 99/1/0.2). The pure fractions were collectedand evaporated, yielding 2.4 g (11%) of(±)-4-[(4-chlorophenyl)(1,2-dihydro-1-methyl-2-oxo-4-phenyl-6-quinolinyl)hydroxymethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide(interm. 3-b).

EXAMPLE A.4

Compound (3) (3 g) was added at room temperature to thionyl chloride (25ml). The mixture was stirred and refluxed at 40° C. overnight. Thesolvent was evaporated till dryness. The product was used withoutfurther purification, yielding 3.49 g of(±)-4-(3-chlorophenyl)-1-methyl-6-[(1-(4-methylphenyl)-1-(4-methyl-4H-pyrrol-3-yl)ethyl]-2(1H)-quinolinonehydrochloride (interm. 4).

EXAMPLE A.5

a) Toluene (1900 ml) was stirred in a round-bottom flask (5 l) using awater separator. (4-Chlorophenyl)(4-nitrophenyl)methanone (250 g) wasadded portionwise. p-Toluene-sulfonic acid (54.5 g) was addedportionwise. Ethylene glycol (237.5 g) was poured out into the mixture.The mixture was stirred and refluxed for 48 hours. The solvent wasevaporated. The residue was dissolved into ethyl acetate (5 l) andwashed twice with a K₂CO₃ 10% solution. The organic layer was separated,dried, filtered and the solvent was evaporated. The residue was stirredin DIPE, filtered off and dried (vacuum, 40° C., 24 hours), yielding 265g (91%) of 2-(4-chlorophenyl)-2-(4-nitrophenyl)-1,3-dioxolane (interm.5-a).

b) Sodium hydroxide (16.4 g) and (3-methoxyphenyl)acetonitrile (20.6 ml)were added at room temperature to a solution of interm. (5-a) (25 g) inmethanol (100 ml) and the mixture was stirred at room temperatureovernight. Water was added, the precipitate was filtered off, washedwith cold methanol and dried. The product was used without furtherpurification, yielding 30 g (90%) of5-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-3-(3-(methoxyphenyl)-2,1-benzisoxazole(interm. 5-b).

c) Interm. (5-b) (30 g) in THF (250 ml) was hydrogenated with palladiumon carbon (3 g) as a catalyst at room temperature for 12 hours under a2.6 10⁵ Pa pressure in a Parr apparatus. After uptake of H₂ (1equivalent), the catalyst was filtered through celite and the filtratewas evaporated till dryness. The product was used without furtherpurification, yielding 31.2 g (100%) of(3-methoxyphenyl)[2-amino-5-[2-(4-chloro-phenyl)-1,3-dioxolan-2-yl]phenyl]methanone(interm. 5-c).

d) Acetic anhydride (13.9 ml) was added to a solution of interm. (5-c)(31.2 g) in toluene (300 ml) and the mixture was stirred and refluxedfor 2 hours. The mixture was evaporated till dryness and the product wasused without further purification, yielding 36.4 g (100%) ofN-[2-(3-methoxybenzoyl)-4-[2-(4-chlorophenyl)1,3-dioxolan-2-yl]phenyl]acetamide(interm. 5-d).

e) Potassium tert-butoxide (33 g) was added portionwise at roomtemperature to a solution of interm. (5-d) (36.4 g) in1,2-dimethoxyethane (350 ml) and the mixture was stirred at roomtemperature overnight. The mixture was hydrolized and extracted withDCM. The organic layer was dried, filtered off and evaporated tilldryness. The product was used without further purification, yielding 43g of6-[2-(4-chloro-phenyl)-1,3-dioxolan-2-yl]-4-(3-methoxyphenyl)-2(1H)-quinolinone(interm. 5-e).

f) A mixture of interm. (5-e) (43 g) in HCl (3N, 400 ml) and methanol(150 ml) was stirred and refluxed overnight. The mixture was cooled andfiltered off. The precipitate was washed with water and diethyl etherand dried. The product was used without further purification, yielding27 g (94%) of 6-(4-chlorobenzoyl)-4-(3-methoxyphenyl)-2(1H)-quinolinone(interm. 5-f).

g) Methyl iodide (1.58 ml) was added to a solution of interm. (5-f) (7.6g) and benzyl-triethylammonium chloride (BTEAC) (2.23 g) in THF (80 ml)and sodium hydroxide (40%, 80 ml). The mixture was stirred at roomtemperature for 2 hours. Water was added and the mixture was extractedwith ethyl acetate. The organic layer was dried, filtered, and thesolvent was evaporated. The residue was purified by flash columnchromatography over silica gel (eluent: DCM 100%). The desired fractionswere collected and the solvent was evaporated, yielding 7.1 g (90%) of6-(4-chlorobenzoyl)-4-(3-methoxyphenyl)-1-methyl-2(1H)-quinolinone(interm. 5-g).

EXAMPLE A.6

a)3-(3-Chlorophenyl)-5-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-2,1-benzisoxazole(interm. 6-a) was prepared analogous as intermediate (5-b).

b) A mixture of intermediate (6-a) (30 g) in HCl 3 N (220 ml) andmethanol (165 ml), was stirred at 100° C. for 5 hours. The mixture waspoured into ice and basified with NH₃ (aq.). The precipitate wasfiltered off, washed with water and diethyl ether and dried, yielding24.9 g (93%) of(4-chlorophenyl)[3-(3-chlorophenyl)-2,1-benzisoxazol-5-yl]methanone(interm. 6-b). The product was used without further purification.

c) Butyllithium in hexanes (10 ml) was added slowly at −70° C. under N₂flow to a solution of 1-methylimidazole (1.31 g) in THF (30 ml). Themixture was stirred at −70° C. for 45 minutes. Chlorotriethylsilane (2.7ml) was added. The mixture was allowed to warm to 15° C. and cooled to−70° C. Butyllithium (10 ml) was added slowly. The mixture was stirredat −70° C. for 1 hour, allowed to warm to −15° C. and cooled to −70° C.A solution of intermediate (6-b) (4.9 g) in THF (60 ml) was added. Themixture was stirred at −70° C. for 30 minutes, then hydrolyzed withwater, extracted with ethyl acetate and decanted. The organic layer wasdried, filtered and the solvent was evaporated. The residue (8.2 g) waspurified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 96/4/0.2) and crystallized from 2-propanone/diethylether. The precipitate was filtered off and dried, yielding 1.5 g (25%)of(±)-3-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-2,1-benzisoxazole-5-methanol(interm. 6-c).

d) TiCl₃/15% in H₂O (200 ml) was added at room temperature to a solutionof intermediate (6-c) (38 g) in THF (300 ml). The mixture was stirred atroom temperature for 90 minutes. The mixture was poured out on ice,basified with K₂CO₃, filtered over celite, washed with ethyl acetate anddecanted. The organic layer was dried, filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.1 and 95/5/0.1), yielding18.7 g (49%) of(±)-[2-amino-5-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]phenyl](3-chlorophenyl)methanone(interm. 6-d).

B. Preparation of the Final Compounds

EXAMPLE B.1

1-Methylimidazole (4.69 ml) in tetrahydrofuran (100 ml) was stirred at−78° C. A solution of butyllithium in hexanes (2.5 M) (36.7 ml) wasadded dropwise and the mixture was stirred at −78° C. for 15 minutes.Chlorothiethylsilane (9.87 ml) was added and the mixture was brought toroom temperature. The mixture was cooled till −78° C., a solution ofbutyllithium in hexanes (2.5 M) (36.7 ml) was added dropwise, themixture was stirred at −78° C. for 1 hour and brought till −15° C. Themixture was cooled till −78° C., a solution of intermediate (1-d) (20 g)in THF (40 ml) was added and the mixture was brought to roomtemperature. The mixture was hydrolized at 0° C. and extracted withethyl acetate. The organic layer was dried, filtered off and evaporatedtill dryness, yielding 36 g of product. The product was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH97/3/0.1). The pure fractions were collected, evaporated, andcrystallized from 2-propanone, CH₃OH and (C₂H₅)₂O. The precipitate wasfiltered off, washed with (C₂H₅)₂O and dried, yielding 12.4 g (52%) of(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone;(comp. 3, mp.233.6° C.).

In a similar way, but using intermediate (5-g) or intermediate (1-e)instead of intermediate (1-d), respectively(±)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-methoxyphenyl)-1-methyl-2(1H)-quinolinone(comp. 36) and(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-3,4-dihydro-1-methyl-2(1H)-quinolinone(comp. 127) were prepared.

EXAMPLE B.2

Hydrochloric acid (60 ml) was added to a solution of intermediate (2)(2.5 g) in THF (10 ml) and the mixture was stirred and heated at 100° C.for 3 hours. The mixture was cooled, the precipitate was filtered off,washed with water, then with diethyl ether and dried, yielding 2.7 g(100%) of(±)-6-[(1-butyl-1H-imidazol-5-yl)-(4-chloro-phenyl)hydroxymethyl]-4-(3-chlorophenyl)-2(1H)-quinolinone(comp. 8).

EXAMPLE B.3

Sodium hydride (0.28 g) was added to a mixture of compound (3) (3 g) inDMF (50 ml) under N₂ and the mixture was stirred for 15 minutes.Iodomethane (1.5 ml) was added and the mixture was stirred at roomtemperature for 1 hour. The mixture was hydrolized and extracted withdiethyl ether and methanol. The organic layer was dried, filtered offand evaporated till dryness, yielding 4.4 g of residue. The residue waspurified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 95.5/4.5/0.2). The pure fractions were collected andevaporated. The product was converted into the ethanedioic acid salt(1:1) in 2-propanone and filtered off. The residue was crystallized from2-propanone, diethyl ether and DIPE. The precipitate was filtered off,washed with diethyl ether, dried and recrystallized from 2-propanone,methanol and DIPE. The precipitate was filtered off, washed with diethylether and dried, yielding 0.95 g (25%) of(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)methoxy(1-methly-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinoneethanedioate (1:1).dihydrate; (comp. 4, mp. 154.6° C.).

EXAMPLE B.4

Iodomethane (0.38 ml) was added dropwise at room temperature to asolution of compound (8) (2.44 g) and N,N,N-triethylbenzenemethanaminiumchloride (0.54 g) in tetrahydrofuran (30 ml) and sodium hydroxide (40%)(30 ml) and the mixture was stirred at room temperature for 3 hours.Water was added and the mixture was extracted with ethyl acetate. Theorganic layer was dried, filtered off and evaporated. The residue waspurified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 96.5/3.5/0.1). The pure fractions were collected,evaporated and crystallized from 2-propanone and DIPE. The precipitatewas filtered off, washed with diethyl ether and dried, yielding 1.4 g(56%) of(±)-4-(3-chlorophenyl)-6-[(1-butyl-1H-imidazol-5-yl)(4-chlorophenyl)hydroxymethyl]-1-methyl-2(1H)-quinolinone; (comp. 9, mp. 174.6° C.).

EXAMPLE B.5

Iodomethane (1.4 ml) was added to a mixture of(±)-6-[(4-chlorophenyl)-1H-imidazol-4-ylmethyl]-1-methyl-4-phenyl-2(1H)-quinolinone(7.5 g) and benzyltriethylammonium chloride (2 g) in THF (75 ml) andsodium hydroxide (75 ml) and the mixture was stirred at room temperaturefor 1 hour. Water was added and the mixture was extracted with ethylacetate. The organic layer was dried, filtered off and evaporated tilldryness. The residue was purified by column chromatography over silicagel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 98.5/1.5/0.1). The pure fractions werecollected and evaporated. Fraction 1 (3.5 g) was recrystallized fromdiethyl ether, yielding 3.3 g (42%) of(±)-6-[(4-chlorophenyl)(1-methyl-1H-imidazol-4-yl)methyl]-1-methyl-4-phenyl-2(1H)-quinolinone;mp. 149.9° C (comp. 44). Fraction 2 was recrystallized from 2-propanone,methanol and diethyl ether, yielding 1.6 g (20%) of(±)-6-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-4-phenyl-2(1H)-quinolinone(comp. 2, mp. 96.8° C.).

EXAMPLE B.6

Sodium borohydride (5.6 g) was added portionwise at 0° C. under N₂ tocompound (3) (7.2 g) dissolved in trifluoroacetic acid (150 ml) and themixture was stirred at room temperature overnight. The mixture waspoured into ice, basified with NaOH 3N, then concentrated NaOH andextracted with ethyl acetate. The organic layer was dried, filtered offand evaporated till dryness. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 95/5). The purefractions were collected and evaporated, yielding 4.3 g (62%) offraction 1; 0.2 g (3%) of fraction 2 and 2 g (29%) of fraction 3.Fraction 1 was converted into the ethanedioic acid salt (1:1) in2-propanone and diethyl ether. The precipitate was filtered off, washedwith diethyl ether and dried, yielding 4.7 g (55%) of(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinoneethanedioate(1:1).mono-hydrate (comp. 5, mp. 157.4° C.).

EXAMPLE B.7

A solution of compound 90 (4.2 g) in 1,2-dimethoxyethane (70 ml) wasstirred under N₂ for 30 minutes. Iodomethane (0.83 ml), followed bypotassium tert-butoxide (2 g) were added portionwise and the mixture wasstirred at room temperature for 30 minutes. Water was added and themixture was extracted with ethyl acetate. The organic layer was dried,filtered off and evaporated. The residue was purified by columnchromatography over silica gel (eluent:cyclohexane/2-propanol/NH₄OH85/5/0.5 to 80/20/1) and converted into the ethanedioic acid salt,crystallized from 2-propanone and filtered off, yielding 1.16 g (23.6%)of(±)-4-(3-chlorophenyl)-6-[1-(4-chloro-phenyl)-1-(1-methyl-1H-imidazol-5-yl)ethyl]-1-methyl-2(1H)-quinolinone.ethanedioate(1:1); (comp. 12, mp. 203.9° C.).

In a similar way, but replacing iodomethane by dichloromethane ordibromomethane, respectively(±)-6-[2-chloro-1-(4-chlorophenyl)-1-(1-methyl-1H-imidazol-5-yl)ethyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinoneethanedioate (1:1) (comp. 69) and(±)-6-[2-bromo-1-(4-chlorophenyl)-1-(1-methyl-1H-imidazol-5-yl)ethyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone(comp. 70) were prepared.

EXAMPLE B.8

a) Compound (3) (3 g) was separated (into its enantiomers) and purifiedby high-performance liquid chromatography over Chiracel OD (20 μm;eluent:hexane/ethanol 50/50). The pure (A)-fractions were collected, andthe solvent was evaporated, yielding 1.6 g ((A); LCI:>99%). The pure(B)-fractions were collected, and the solvent was evaporated, yielding1.5 g ((B); LCI:>99%). The (A)-residue was dissolved in 2-propanol andconverted into the ethanedioic acid salt (1:1). The precipitate wasfiltered off and dried, yielding 0.6 g (17%) of(+)-4-(3-chlorophenyl)-6-[(4-chloro-phenyl)-hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-20quinolinoneethanedioate (1:1); [α]_(D) ²⁰=+17.96° (c=1% in methanol) (comp. 23).The (B)-residue was dissolved in 2-propanol and converted into theethanedioic acid salt (1:1). The precipitate was filtered off and dried,yielding 0.6 g (17%)(−)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinoneethanedioate(1:1); [α]_(D) ²⁰=−18.87° (c=1% (w/v) in methanol) (comp.24).

b) Compound 14 (4 g) was separated (into its enantiomers) and purifiedby chiral column chromatography over Chiralcel OD (25 cm; eluent: 100%ethanol; flow: 0.5 ml/min; wavelength: 220 nm). The pure (A)-fractionswere collected, and the solvent was evaporated. This residue wasdissolved in DCM (100 ml), filtered, and the filtrate was evaporated.The residue was stirred in DIPE (100 ml), filtered off and dried,yielding 1.3 g(−)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chloro-phenyl)-1-methyl-2(1H)-quinolinone([α]_(D) ²⁰=−6.16° (c=0.67% (w/v) in methanol)(comp. 74).

The pure (B)-fractions were collected and evaporated. The residue wascrystallized from 2-propanol. The precipitate was filtered off, yielding1.3 g(+)-6-[amino(4-chloro-phenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone([α]_(D) ²⁰=+22.860° (c=0.98% (w/v) in methanol) (comp. 75).

EXAMPLE B.9

Air was bubbled through a solution of compound (47) (3.6 g) in THF (40ml) for 30 minutes. 2-Methyl-2-propanol potassium salt (4.4 g) wasadded. The mixture was stirred at room temperature for 3 hours,hydrolyzed and then extracted with DCM. The organic layer was separated,dried, filtered and the solvent was evaporated, yielding 2.9 g ofproduct. The product was purified by column chromatography over silicagel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97.5/2.5/0.1). The pure fractions werecollected and the solvent was evaporated. The residue was crystallizedfrom 2-propanone/DIPE. The precipitate was filtered off and dried,yielding 1.3 g (35%) of(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-4-yl)methyl]-1-methyl-2(1H)-quinolinone(comp. 48).

EXAMPLE B.10

A mixture of(+)-4-[(4-chlorophenyl)(1,2-dihydro-1-methyl-2-oxo-4-phenyl-6-quinolinyl)hydroxymethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide(2.4 g) in hydrochloric acid (10 ml), water (30 ml) and methanol (15 ml)was stirred and heated at 110° C. for 14 hours. The mixture was cooled,basified with NH₃ (aq.) and extracted with DCM. The organic layer wasdried, filtered off and evaporated till dryness. The residue waspurified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.2). The pure fractions were collected andevaporated. The residue (1.25 g) was crystallized from 2-propanone/DIPE,yielding 1 g (48.3%) of(±)-6-[(4-chlorophenyl)hydroxy(1H-imidazol-4-yl)methyl]-1-methyl-4-phenyl-2(1H)-quinolinonemonohydrate (comp. 43).

EXAMPLE B.11

Compound (3) (4 g) was dissolved in DCM (10 ml) and acetic acid (5.6 ml)at 45° C. Zinc chloride (5.5 g), followed by cyanoacetic acid (3.5 g)were added. The mixture was stirred at 120° C. for 3 hours and then at160° C. for 10 hours. Water was added and the mixture was extracted withDCM. The organic layer was washed with K₂CO₃10%, dried, filtered, andthe solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 96/4/0.2),crystallized from 2-propanone/DIPE, filtered off and dried, yielding1.95 g (45%) of(±)-4-(3-chlorophenyl)-β-(4-chlorophenyl)-1,2-dihydro-1-methyl-β-(1-methyl-1H-imidazol-5-yl)-2-oxo-6-quinolinepropanenitrile;(comp. 25, mp. 151.3° C.).

EXAMPLE B.12

Sulfuric acid (1 ml) was added dropwise to acetonitrile (30 ml), whilestirring. Compound 3 (3 g) was added. The mixture was stirred at 80° C.for 3 hours and then cooled. K₂CO₃ 10% was added and the mixture wasextracted with ethyl acetate. The organic layer was separated, dried,filtered and the solvent was evaporated till dryness. The residue (3.58g) was dissolved in 2-propanone and converted into the ethanedioic acidsalt (1:1)., The precipitate was filtered off, dried and crystallizedfrom 2-propanone/CH₃OH. The precipitate was filtered off and dried,yielding 3.5 g (92%) of(±)-N-[(4-chlorophenyl)[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl](1-methyl-1H-imidazol-5-yl)methyl]acetamideethanedioate (1:1) (comp. 56).

EXAMPLE B.13

NH₃ (aq.) (40 ml) was added at room temperature to a mixture ofintermediate 4 (7 g) in THF (40 ml). The mixture was stirred at 80° C.for 1 hour, then hydrolyzed and extracted with DCM. The organic layerwas separated, dried, filtered and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:toluene/2-propanol/NH₄OH 80/20/1). The pure fractions were collected andthe solvent was evaporated, yielding 4.4 g(±)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone(comp. 14).

EXAMPLE B.14

A solution of compound 36 (6.2 g) in DCM (140 ml) was cooled andtribromoborane (32 ml) was added dropwise. The mixture was stirred atroom temperature for tho days.

The mixture was poured out into ice water, basified with NH₃ (aq.) andextracted with CH₂Cl₂/CH₃OH. The organic layer was separated, dried,filtered and the solvent was evaporated till dryness, yielding 6 g(100%) of(±−)-6-[(4-chlorophenyl)-hydroxy-(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-hydroxyphenyl)-1-methyl-2(1H)-quinolinone(comp. 54).

EXAMPLE B.15

A mixture of compound 54 (2.5 g), 2-chloro-N,N-dimethyl-ethanamine (1.9g) and potassium carbonate (2.2 g) in ACN (50 ml) and DMF (50 ml) wasstirred at 100° C. overnight. The solvent was evaporated till dryness.The residue was taken up in CH₂Cl₂/water and decanted. The organic layerwas dried, filtered and the solvent was evaporated. The residue (2.7 g)was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.1 to 90/10/0.1). The pure fractions werecollected and the solvent was evaporated. The residue was converted intothe ethanedioic acid salt (1:1) in 2-propanone. The precipitate wasfiltered off, washed with 2-propanone/diethyl ether and dried. Theresidue was converted into the free base. The precipitate was filteredoff and dried. The residue was crystallized from diethyl ether. Theprecipitate was filtered off and dried, yielding 0.35 g (12%) of(±)-6-[(4-chloro-phenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-[3-[2-(dimethylamino)ethoxy]-phenyl]-1-methyl-2(1H)-quinolinone(comp. 62).

EXAMPLE B.16

P₄S₁₀ (12 g) was added to a mixture of compound 90 (6 g) in pyridine (72ml). The mixture was stirred and refluxed for 6 hours. Ice water wasadded. The precipitate was filtered off, washed with water and taken upin DCM. The organic layer was separated, dried, filtered and the solventwas evaporated till dryness. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH97.5/2.5/0.1). The pure fractions were collected and the solvent wasevaporated. The residue was crystallized from 2-propanone/diethyl ether.The precipitate was filtered off and dried, yielding 1 g of(±)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinethione(comp. 128).

EXAMPLE B.17

A mixture of ethyl malonyl chloride (6.4 ml) in DCM (50 ml) was addeddropwise at room temperature to a solution of intermediate (6-d) (15 g)and pyridine (10.7 ml) in DCM (150 ml). The mixture was stirred at roomtemperature overnight. Water was added and the mixture was decanted. Theorganic layer was dried, filtered and the solvent was evaporated. Theresidue (21 g) was purified by column chromatography over silica gel(eluent: CH₂Cl₂/2-propanol/NH₄OH 92/8/0.4). The desired fractions werecollected and the solvent was evaporated, yielding 10.9 g (60%) of(±)-ethyl4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,2-dihydro-2-oxo-3-quinolinecarboxylate(comp. 144).

EXAMPLE B.18

a) A mixture of benzoyl chloride (3.1 ml) in DCM (25 ml) was addeddropwise at room temperature to a solution of interm. (6-d) (7 g) andpyridine (5 ml) in DCM (70 ml). The mixture was stirred at roomtemperature for 45 minutes. Water was added and the mixture wasdecanted. The organic layer was dried, filtered and the solvent wasevaporated, yielding 8.8 g of(±)-N-[2-(3-chlorobenzoyl)-4-[(4-chlorophenyl)-hydroxy(1-methyl-1H-imidazol-5-yl)methyl]phenyl]benzeneacetamide(interm. 7). The product was used without further purification.

b) Potassium tert-butoxide (8.7 g) was added to a mixture ofintermediate 7 (8.8 g) in DME (70 ml). The mixture was stirred at 50° C.for 3 hours. Water (5 ml) was added and the solvent was evaporated,yielding 8.5 g of(±)-4-(3-chlorophenyl)-6-[(4-chloro-phenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-3-phenyl-2(1H)-quinolinone(comp. 140).

EXAMPLE B.19

NH₃ (aq.) (150 ml) was cooled to 5° C. A solution of(±)-4-(3-chlorophenyl)-1-methyl-6-[1-(4-methylphenyl)-1-(4-methyl-4H-pyrrol-3-yl)ethyl]-2(1H)-quinolinonehydrochloride (16.68 g) in THF (150 ml) was added. The mixture wasstirred at room temperature for 2 hours, decanted and extracted withethyl acetate. The organic layer was dried, filtered and the solvent wasevaporated till dryness. The reaction was carried out twice. Theresidues were combined and purified by column chromatography over silicagel (eluent: toluene/2-propanol/NH₄OH 70-29-1). The pure fractions werecollected and the solvent was evaporated. The residue was crystallizedfrom CH₂Cl₂/CH₃OH/CH₃CN. The precipitate was filtered off and the motherlayer was evaporated till dryness, purified by column chromatography(eluent: CH₃OH/NH₄OAc (0.5% in H₂O) 70/30). Two pure fractions werecollected and their solvents were evaporated till dryness. Fraction 2was recrystallized from CH₂Cl₂/diethyl ether. The precipitate wasfiltered off and dried, yielding 0.8 g of(±)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-3-chloro-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone(comp. 143).

EXAMPLE B.20

Sulfuric acid (1 ml) was added at room temperature to a solution ofcompound 3 (3.5 g) in methoxyacetonitrile (10 ml) and the mixture wasstirred and heated at 80° C. for 3 hours. The mixture was couled, pouredinto ice, basified with NH₃ (aq.) and filtered, off. The precipitate wastaken up in DCM. The organic layer was separated, dried, filtered andthe solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 96/4/0.3).The pure fractions were collected and the solvent was evaporated. Theresidue was converted into the hydrochloric acid salt (1:1) andcrystallized from ACN. The precipitate was filtered off and dried,yielding 2.5 g (58%) of(±)-N-[(4-chlorophenyl)[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl](1-methyl-1H-imidazol-5-yl)methyl]-2-methoxyacetamidemonohydrochloride (comp. 89).

EXAMPLE B.21

A solution of intermediate (4) (3.3 g) in THF (10 ml) was added dropwiseat room temperature to a solution of methanamine in water (40 ml). Themixture was stirred at 80° C. for 45 minutes, taken up in water andextracted with DCM. The organic layer was separated, dried, filtered andthe solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.3 and95/5/0.3). The pure fractions were collected and the solvent wasevaporated. The residue was crystallized from diethyl ether. Theprecipitate was filtered off and dried, yielding 0.89 g (28%) of(±)-4-(3-chlorophenyl)-6-[(4-chloro-phenyl)(methylamino)-(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinonemonohydrate (comp. 61).

Tables 1 to 8 list the compounds that were prepared according to one ofthe above Examples and table 9 lists both the experimental (columnheading “exp.”) and theoretical (column heading “theor.”) elementalanalysis values for carbon, hydrogen and nitrogen of the compounds asprepared in the experimental part hereinabove.

TABLE 1

Co. Ex. No. No. R¹ R^(4a) R⁸ Physical data 3 B.1 CH₃ CH₃ OH mp. 233.6°C. 4 B.3 CH₃ CH₃ OCH₃ mp. 140-160° C.; .C₂H₄O₄.H₂O 5 B.6 CH₃ CH₃ H mp.165° C.; .C₂H₄O₄.H₂O 6 B.5 CH₃ CH₂CH₃ H mp. 180° C.; .C₂H₂O₄.1/2H₂O 7B.2 H CH₃ H mp. 260° C. 8 B.2 H (CH₂)₃CH₃ OH — 9 B.4 CH₃ (CH₂)₃CH₃ OHmp. 174° C. 10 B.3 H CH₃ OCH₂COOCH₂CH₃ mp. 185° C.; .3/2C₂H₂O₄ 11 B.3CH₃ CH₃ O(CH₂)₂N(CH₃)₂ mp. 120° C. 12 B.7 CH₃ CH₃ CH₃ mp. 210° C.;.C₂H₄O₄ 13 B.7 CH₃ CH₃ CH₂CH₃ mp. 196° C. .C₂H₂O₄ 14 B.13 CH₃ CH₃ NH₂mp. 220° C. 72 B.13 CH₃ CH₃ NH₂ .3/2-(E)-C₄H₄O₄ 73 B.13 CH₃ CH₃ NH₂.2HCl 74 B.8b CH₃ CH₃ NH₂ (−)- 75 B.8b CH₃ CH₃ NH₂ (+)-; mp. 232.4° C.15 B.3 CH₃ CH₃ O(CH₂)₃OH mp. 135° C. 16 B.3 CH₃ CH₃ O(CH₂)₂CH₃ mp. 180°C.; .C₂H₂O₄.3/2(H₂O) 17 B.3 CH₃ CH₃ O(CH₂)₂O—C₆H₅ mp. 144° C.;.3/2(C₂H₂O₄) 18 B.2 H CH(CH₃)₂ OH — 19 B.4 CH₃ CH(CH₃)₂ OH mp. 254° C.20 B.2 H (CH₂)₂OCH₃ OH mp. 112° C. 21 B.4 CH₃ (CH₂)₂OCH₃ OH mp. 192° C.22 B.3 CH₃ CH₃ O(CH₂)₂OH mp. 198° C. 23 B.8a CH₃ CH₃ OH mp. 150-200° C.;(+)-; .C₂H₂O₄ 24 B.8a CH₃ CH₃ OH mp. 150-200° C.; (−)-; .C₂H₂O₄ 25 B.11CH₃ CH₃ CH₂—CN mp. 154° C. 27 B.2 H (CH₂)₃OCH₃ OH — 28 B.4 CH₃(CH₂)₃OCH₃ OH mp. 196° C.; .H₂O 29 B.3 CH₃ CH₃ O(CH₂)₃OCH₂CH₃ mp. 105°C.; .3/2(H₂O) 31 B.2 H CH₃ OH >260° C. 32 B.6 CH₃ (CH₂)₂OCH₃ H mp. 140°C.; .3/2(C₂H₂O₄) 33 B.6 CH₃ (CH₂)₃OCH₃ H mp. 180° C.; .HCl 56 B.12 CH₃CH₃ —NHCOCH₃ .C₂H₂O₄ 58 B.11 CH₃ CH₃ —CH₂COOCH₂CH₃ .C₂H₂O₄.3/2(H₂O) 60B.11 CH₃ CH₃ 1-imidazolyl — 61 B.21 CH₃ CH₃ —NH—CH₃ mp. 164° C. 65 B.2 H(CH₂)₃SOCH₃ OH .H₂O 66 B.13 CH₃ CH₃ —N(CH₃)₂ .2C₂H₂O₄.H₂O mp. 160° C. 67B.13 CH₃ CH₃ —NH—(CH₂)₂OCH₃ mp. 216° C. 68 B.13 CH₃ CH₃ —NH—(CH₂)₂—OH —69 B.7 CH₃ CH₃ —CH₂Cl .2C₂H₂O₄ mp. 220° C. 70 B.7 CH₃ CH₃ —CH₂Br — 71 *CH₃ CH₃ —CH₂OH .2C₂H₂O₄ 76 B.4 —(CH₂)₂OCH₃ CH₃ OH mp. 150° C. 77 * CH₃CH₃ —CH₂OCH₃ .2C₂H₂O₄ mp. 166° C. 78 B.13 CH₃ CH₃ —NH—OCH₃ mp. 170° C.79 B.20 CH₃ CH₃ —NH—CONH₂ .2H₂O 80 ** CH₃ CH₃ —CH₂CONH₂ — 81 B.13 CH₃CH₃ —NH—OH — 82 B.13 CH₃ CH₃ —NH(CH₂)₂N(CH₃)₂ — 83 B.4 (CH₂)₂N(CH₃)₂ CH₃OH .3/2C₂H₂O₄ .3/2H₂O mp. 200° C. 84 * CH₃ CH₃ —CH₂N(CH₃)₂ .C₂H₂O₄ mp.210° C. 85 B.4 CH₃ CH₃ —N(CH₃)₂ — 86 B.4 CH₃ CH₃ NHCOCH₂N(CH₃)₂ — 87 B.4CH₃ CH₃ —NH(CH₂)₉CH₃ — 88 B.4 CH₃ CH₃ —NH(CH₂)₂NH₂ — 89 B.20 CH₃ CH₃—NHCOCH₂OCH₃ .HCl mp. 220° C. 90 B.6 CH₃ CH₃ H — 91 B.20 CH₃ CH₃—NHCOCH₂C₆H₅ .C₂H₂O₄.H₂O mp. 170° C. 92 B.20 CH₃ CH₃ —NHCOC₆H₅ mp. 242°C. 93 B.20 CH₃ CH₃ —NHCOCONH₂ .C₂H₂O₄.H₂O mp. 186° C. 94 B.13 CH₃ CH₃—NHC₆H₅ mp. 165° C. *prepared by functional-group transformation ofcompound 70 **prepared by functional-group transformation of compound 25

TABLE 2

Co. Ex. No. No. R¹ R² R^(4a) R⁵ R⁸ Physical data 1 B.1 CH₃ H CH₃ H OHmp. >250° C. 2 B.5 CH₃ H CH₃ H H mp. 100-110° C. 26 B.1 CH₃ 3-Cl CH₃2-CH₃ OH mp. 200° C. 30 B.6 CH₃ 3-Cl CH₃ 2-CH₃ H mp. 120-140° C.;.3/2(C₂H₂O₄).H₂O 34 B.1 CH₃ 3-O—CH₂—CH₃ CH₃ H OH mp. 190° C. 35 B.6 CH₃3-O—CH₂—CH₃ CH₃ H H mp. 160-180° C.; .HCl.H₂O 36 B.1 CH₃ 3-O—CH₃ CH₃ HOH mp. 210° C. 37 B.1 CH₃ 3-O—(CH₂)₂—CH₃ CH₃ H OH mp. 150-160° C. 38 B.1CH₃ 3-O—(CH₂)₃—CH₃ CH₃ H OH mp. 150-160° C. 49 B.1 CH₃ 4-O—CH₂—CH₃ CH₃ HOH mp. 184.2° C. 50 B.1 CH₃ 3-O—CH—(CH₃)₂ CH₃ H OH mp. 147.1° C. 51 B.6CH₃ 3-O—(CH₂)₃—CH₃ CH₃ H H mp. 164.2° C.; .3/2(C₂H₂O₄) 52 B.6 CH₃3-O—(CH₂)₂—CH₃ CH₃ H H .3/2(C₂H₂O₄) 53 B.6 CH₃ 3-O—CH—(CH₃)₂ CH₃ H H mp.133.9° C.; .C₂H₂O₄.H₂O 54 B.14 CH₃ 3-OH CH₃ H OH — 64 B.10 CH₃ 3-OH CH₃H OH .HCl.H₂O 55 B.6 CH₃ 3-OH CH₃ H H mp. >250° C. 57 B.1 CH₃ 2-OCH₂CH₃CH₃ H OH — 59 B.13 CH₃ 3-OCH₂CH₃ CH₃ H NH₂ — 95 B.8a CH₃ 3-OCH₂CH₃ CH₃ HNH₂ (A) 96 B.8a CH₃ 3-OCH₂CH₃ CH₃ H NH₂ (B) 62 B.15 CH₃ 3-O(CH₂)₂N(CH₃)₂CH₃ H OH — 63 B.11 CH₃ 3-O(CH₂)₂—OH CH₃ H OH — 97 B.1 CH₃ 3-CH₂CH₃ CH₃ HOH — 98 B.13 CH₃ 3-CH₂CH₃ CH₃ H NH₂ mp. 240° C. 99 B.1 CH₃ 3-(CH₂)₂CH₃CH₃ H OH — 100 B.13 CH₃ 3-(CH₂)₂CH₃ CH₃ H NH₂ — 101 * CH₃ 3-O—(CH₂)₂OCH₃CH₃ H OH .3/2(C²⁻H₂O₄) mp. 193° C. 102 B.1 CH₃ 3-CH₃ CH₃ H OH mp. >250°C. 103 B.13 CH₃ 3-CH₃ CH₃ H NH₂ — 104 B.1 CH₃ 3-Br CH₃ H OH — 105 B.13CH₃ 3-Br CH₃ H NH₂ — 106 B.1 CH₃ 3-O—CF₃ CH₃ H OH — 107 B.13 CH₃ 3-O—CF₃CH₃ H NH₂ mp. 168° C. 108 B.1 CH₃ 3-C₆H₅ CH₃ H OH — 109 B.13 CH₃ 3-C₆H₅CH₃ H NH₂ — 110 B.1 CH₃ 3-F CH₃ H OH — 111 B.13 CH₃ 3-F CH₃ H NH₂mp. >250° C. 112 B.1 CH₃ 3-(E)- CH₃ H OH mp. >250° C. CH═CH—CH₃ 113 B.2H 3-Cl CH₃ 3-Cl OH — 114 B.4 CH₃ 3-Cl CH₃ 3-Cl OH — 115 B.1 CH₃ 3-Cl H3-CH₃ OH — 116 B.4 CH₃ 3-Cl CH₃ 3-CH₃ OH — 117 ** CH₃ 3-CN CH₃ H OH —160 B.1 CH₃ 3-CF₃ CH₃ H OH — *prepared by functional-grouptransformation of compound 54 **prepared by functional-grouptransformation of compound 104

TABLE 3

Co. Ex. No. No. R¹ R⁸ Physical data 39 B.1CH₂CONHCH(COOCH₃)(CH₂CH(CH₃)₂) H mp. 240° C. (S) 40 B.4 CH₂-2-quinolinylH mp. 240° C.; .2 HCl 41 B.4 CH₂CONHCH(COOCH₃)(CH₂CH(CH₃)₂) OH mp. >260°C. (S)

TABLE 4

Co. Ex. No. No. R² R⁴ R^(5a) R⁶ R⁸ Physical data 42 B.6 H H H 4-Cl H mp.170° C.; .C₂H₂O₄.1/2 H₂O 43 B.10 H H H 4-Cl OH mp. 180° C.; .H₂O 44 B.5H H CH₃ 4-Cl H mp. 152° C. 45 B.6 3-Cl H H 4-Cl H mp. 175° C.; .C₂H₂O₄46 B.5 3-Cl H CH₂CH₃ 4-Cl H mp. 132° C.; .C₂H₂O₄ 47 B.5 3-Cl H CH₃ 4-ClH mp. 115° C.; .3/2 C₂H₂O₄ 48 B.9 3-Cl H CH₃ 4-Cl OH mp. 230° C. 118 B.43-Cl 3-CH₃ CH₃ 4-Cl OH mp. 222° C.

TABLE 5

Co. No. Ex. No. —R²—R³— R⁶ R⁸ 119 B.1 —O—CH₂—O— 4-Cl OH 120 B.13—O—CH₂—O— 4-Cl NH₂ 121 B.1 —O—CH₂—CH₂—O— 4-Cl OH 122 B.13 —O—CH₂—CH₂—O—4-Cl NH₂ 123 B.1 —O—CH═CH— 4-Cl OH

TABLE 6

Co. No. Ex. No. X

R² R³ R¹⁶ R⁸ Physical data 124 B.1 O dou- 3-OCH₃ 4-OCH₃ 5-OCH₃ OH mp.ble 230° C. 125 B.13 O dou- 3-OCH₃ 4-OCH₃ 5-OCH₃ NH₂ mp. ble 218° C..C₂H₂O₄ 126 B.1 O single 3-Cl H H OH mp. 160° C. 127 B.1 O single 3-Cl HH OH — 128 B.16 S dou- 3-Cl H H H — ble

TABLE 7

Co. Ex. No. No. R¹ R¹⁷ R¹⁸ R¹⁹ R⁸ Physical data 129 B.17 H CN H H H —130 B.4 CH₃ CN H H H mp. 202° C. 131 B.17 H CN H H OH — 132 B.4 CH₃ CN HH OH — 133 B.17 H CN H H —CH₂CN — 134 B.4 CH₃ CN H H —CH₂CN mp. 138° C.135 B.18 H CH₃ H H OH — 136 B.4 CH₃ CH₃ H H OH — 137 B.13 CH₃ CH₃ H HNH₂ mp. >250° C. 138 B.18 H C₆H₅ H H H — 139 B.4 CH₃ C₆H₅ H H H.3/2(C₂H₂O₄) mp. 180° C. 140 B.18 H C₆H₅ H H OH — 141 B.4 CH₃ C₆H₅ H HOH — 142 B.13 CH₃ C₆H₅ H H NH₂ — 143 B.13 CH₃ Cl H H NH₂ — 144 B.17 H—COOCH₂CH₃ H H OH — 145 B.4 CH₃ —COOCH₂CH₃ H H OH — 146 B.1 CH₃ H 8-CH₃H OH — 147 B.13 CH₃ H 8-CH₃ H NH₂ .H₂O 148 B.1 CH₃ H 7-Cl H OH — 149 B.1CH₃ H 7-CH₃ H OH — 150 B.1 CH₃ H 5-CH₃ H OH — 151 B.1 CH₃ H 8-OCH₃ H OH— 161 B.1 CH₃ H 7-CH₃ 8-CH₃ OH mp. 255° C.

TABLE 8

Co. Ex. No. No. R² R³ R⁶ R⁷ R⁸ Physical data 152 B.1 3-OCH₂CH₃ H4-OCH₂CH₃ H OH .3/2(C₂H₂O₄) 153 B.1 3-Cl H H H OH — 154 B.1 3-Cl H 4-CH₃H OH — 155 B.1 3-Cl H 4-OCH₃ H OH — 156 B.1 3-Cl H 4-CF₃ H OH — 157 B.13-Cl H 2-Cl 4-Cl OH — 158 B.1 3-Cl 5-Cl 4-Cl H OH — 159 B.1

H 4-Cl H OH — 162 B.1 3-Cl H 4-S—CH₃ H OH mp. 169° C. .C₂H₂O₄.H₂O; 163B.1 3-Cl H 4-N(CH₃)₂ H OH mp. decomposes >172° C. 164 B.1 3-Cl H—CH═CH—CH═CH—* OH .C₂H₂O₄ *R⁶ and R⁷ taken together to form a bivalentradical between positions 3 and 4 on the phenyl moiety

TABLE 9 Comp. Carbon Hydrogen Nitrogen No. Exp. Theor. Exp. Theor. Exp.Theor. 57 67.78 69.66 4.82 5.24 7.83 8.40 58 58.59 58.50 4.58 4.76 5.966.20 59 69.68 69.80 5.38 5.45 11.06 11.23 60 65.89 66.67 4.35 4.29 11.3012.96 62 66.51 68.56 5.74 5.75 9.67 10.32 63 66.64 67.50 5.29 5.08 7.638.14 64 62.20 61.60 4.70 4.79 7.97 7.98 65 58.90 59.59 4.42 4.66 6.797.19 68 64.29 65.29 4.87 4.91 10.13 10.50 71 60.68 60.62 3.86 4.24 6.877.07 73 54.33 57.67 4.51 4.30 9.26 9.96 74 66.64 66.26 4.28 4.53 11.3311.45 75 66.26 66.26 4.39 4.53 11.30 11.45 79 59.89 59.16 4.65 4.7912.18 12.32 80 64.27 65.54 4.71 4.55 10.36 10.54 81 64.27 64.17 4.444.39 10.92 11.09 82 65.98 66.43 5.88 5.57 11.61 12.49 85 66.20 67.315.22 5.06 10.44 10.83 86 64.83 64.81 4.96 5.09 12.12 12.19 87 69.6370.58 6.88 6.72 8.70 8.90 88 65.21 65.42 5.10 5.11 13.22 13.15 97 71.3871.97 5.60 5.41 8.17 8.68 98 71.38 72.11 5.58 5.63 11.31 11.60 100 71.9272.50 5.65 5.88 10.92 11.27 103 70.72 71.71 5.42 5.37 11.80 11.95 10460.56 60.63 3.99 3.96 7.84 7.86 105 60.33 60.75 3.72 4.15 10.28 10.49106 62.37 62.29 3.71 3.92 7.71 7.78 108 74.22 74.50 4.94 4.93 7.83 7.90109 74.17 74.64 5.23 5.12 10.60 10.55 110 68.17 68.43 4.28 4.47 8.758.87 115 65.98 66.13 4.08 4.32 8.53 8.57 116 66.49 66.67 4.38 4.60 8.478.33 117 67.97 69.93 4.60 4.40 11.14 11.65 120 67.35 67.40 4.62 4.6511.14 11.23 121 67.32 67.77 4.72 4.71 7.78 8.18 122 67.88 67.90 4.724.91 10.88 10.92 123 69.75 70.23 4.77 4.47 8.06 8.47 128 65.88 66.124.24 4.32 8.37 8.57 132 65.20 65.25 3.77 3.91 10.42 10.87 136 66.7766.67 4.64 4.60 8.34 8.33 142 69.26 70.09 4.42 4.63 9.59 9.91 145 64.3664.06 4.19 4.48 7.49 7.47 148 61.88 61.79 3.65 3.84 7.88 8.01 150 66.5666.67 4.64 4.60 8.08 8.33 151 64.76 64.62 4.86 4.45 7.80 8.07 153 70.9971.13 5.17 4.86 9.25 9.22 154 71.67 71.56 5.08 5.15 9.14 8.94 158 61.7261.79 3.76 3.84 7.96 8.01 159 69.28 69.50 5.21 5.29 10.01 10.13 16062.71 64.19 3.91 4.04 7.36 8.02

C. Pharmacological Example

C.1 Inhibition of Smooth Muscle Cell Proliferation.

The effects of the compounds of the present invention were studied inhuman pulmonary artery smooth muscle cells (PASMC), human coronaryartery smooth muscle cells (CASMC), and rat A10 arterial smooth musclecells growing under standard tissue culture conditions. CASMC and PASMCcell cultures were purchased from Clonetics (San Diego, Calif.). A10smooth muscle cells were purchased from the American Type CultureCollection (Bethesda, Md.). Cells were inoculated at an initial celldensity of 50,000 cells per well in six-well plastic cluster tissueculture dishes in 3.0 ml of complete growth medium. Test compounds weredissolved in dimethysulfoxide (DMSO) and added in a 3 μl volume to eachwell to produce the desired concentrations of said test compound (5, 10,50, 100 and 500 nM final concentrations). Cells were incubated for sixdays. On day 4, fresh medium plus a fresh solution containing the testcompound were added to the cell cultures. On day 6, the growth mediumwas removed by aspiration. The cells were detached by trypsinizing in1.0 ml of trypsin-EDTA solution. The cell suspensions were transferredto 20 ml of an isotonic diluent and 0.5 ml of the diluted cellsuspension was counted with a Coulter particle counter. Cell counts fromtest compound-treated cultures were normalized to cell counts obtainedfrom DMSO-treated controls and expressed as percent inhibition. IC₅₀values (concentration of test compound producing a 50% inhibition ofcell proliferation) were derived from the inhibition data. These resultsare summarized in Table C.1.

TABLE C.1 Inhibition of Smooth Muscle Cell Proliferation IC₅₀ (nM) CellLine Co. No. 75 A10 14 PASMC 24 CASMC 16

What is claimed is:
 1. A method for inhibiting smooth muscle cellproliferation in a warm-blooded animal comprising the step of:introducing a transluminal device into a warm-blooded animal wherein thetransluminal device comprises a therpaeutically effective amount of acompound of formula (I):

a stereoisomeric form thereof, a pharmaceutically acceptable acid orbase addition salt thereof, wherein the dotted line represents anoptional bond; X is oxygen or sulfur; R¹ is hydrogen, C₁₋₁₂alkyl, Ar¹,Ar²C₁₋₆alkyl, quinolinylC₁₋₆alkyl, pyridylC₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl,aminoC₁₋₆alkyl, or a radical of formula —Alk¹—C(═O)—R⁹, —Alk¹—S(O)—R⁹ or—Alk¹—S(O)₂—R⁹, wherein Alk¹ is C₁₋₆alkanediyl, and R⁹ is hydroxy,C₁₋₆alkyl, C₁₋₆alkyloxy, amino, C₁₋₈alkylamino or C₁₋₈alkylaminosubstituted with C ₁₋₆alkyloxycarbonyl; R², R³ and R¹⁶ eachindependently are hydrogen, hydroxy, halo, cyano, C₁₋₆alkyl,C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy,aminoC₁₋₆alkyloxy, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, AR¹,AR²C₁₋₆alkyl, AR²oxy, AR²C₁₋₆alkyloxy, hydroxycarbonyl,C₁₋₆alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C₂₋₆alkenyl, or4,4-dimethyloxazolyl, or when on adjacent positions R² and R³ takentogether may form a bivalent radical of formula —O—CH₂—O—  (a-1),—O—CH₂—CH₂—O—  (a-2), —O—CH═CH—  (a-3), —O—CH₂—CH₂—  (a-4),—O—CH₂—CH₂—CH₂—  (a-5), or —CH═CH—CH═CH—  (a-6); R⁴ and R⁵ eachindependently are hydrogen, halo, AR¹, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, amino,hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylS(O)C₁₋₆alkyl, orC₁₋₆alkylS(O)₂C₁₋₆alkyl; R⁶ and R⁷ each independently are hydrogen,halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxy, Ar²oxy, trihalomethyl,C₁₋₆alkylthio, di(C₁₋₆alkyl)amino, or when on adjacent positions R⁶ andR⁷ taken together may form a bivalent radical of formula—O—CH₂—O—  (c-1), or —CH═CH—CH═CH—  (c-2); R⁸ is hydrogen, C₁₋₆alkyl,cyano, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylcarbonylC₁₋₆alkyl, cyanoC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl, carboxyC₁₋₆alkyl, hydroxyC₁₋₆alkyl,aminoC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆-alkyl, imidazolyl,haloC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, or aradical of formula —O—R¹⁰  (b-1), —S—R¹⁰  (b-2), —N—R¹¹R¹²   (b-3),wherein R¹⁰ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, AR¹,AR²C₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, a radical or formula—Alk²—OR¹³, or —Alk²—NR¹⁴R¹⁵; R¹¹ is hydrogen, C₁₋₁₂alkyl, Ar¹, orAr²C₁₋₆alkyl; R¹² is hydrogen, C₁₋₆alkyl, C₁₋₁₆alkylcarbonyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkylaminocarbonyl, AR¹, AR²C₁₋₆alkyl,C₁₋₆alkylcarbonylC₁₋₆alkyl, a natural amino acid, AR¹carbonyl,AR²C₁₋₆alkylcarbonyl, aminocarbonylcarbonyl,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy, C₁₋₆alkyloxy, aminocarbonyl,di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, amino, C₁₋₆alkylamino,C₁₋₆alkylcarbonylamino, or a radical of formula —Alk²—OR¹³ or—Alk²—NR¹⁴R¹⁵; wherein Alk² is C₁₋₆alkanediyl; R¹³ is hydrogen,C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkyl, AR¹ or AR²C₁₋₆alkyl; R¹⁴is hydrogen, C₁₋₆alkyl, AR¹ or AR²C₁₋₆alkyl; and R¹⁵ is hydrogen,C₁₋₆alkyl, C₁₋₆alkylcarbonyl, AR¹ or AR²C₁₋₆alkyl; R¹⁷ is hydrogen,halo, cyano, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, or AR¹; R¹⁸ is hydrogen,C₁₋₆alkyl, C₁₋₆alkyloxy or halo; R¹⁹ is hydrogen or C₁₋₆alkyl; AR¹ isphenyl or phenyl substituted with C₁₋₆alkyl, hydroxy, amino,C₁₋₆alkyloxy or halo; and AR² is phenyl or phenyl substituted with C₁%alkyl, hydroxy, amino, C₁₋₆alkyloxy or halo.
 2. The method of claim 1wherein the transluminal device is a stent.
 3. The method of claim 1wherein the transluminal device is a catheter.
 4. The method of claim 1wherein in Formula (I) X is oxygen, the dotted line represents a bondand R¹ is hydrogen, C¹⁻⁶alkyl, C₁₋₆alkyloxyC₁₋₆alkyl or mono- ordi(C₁₋₆alkyl)amino C₁₋₆alkyl.
 5. The method of claim 1 wherein inFormula (I) R³ is hydrogen and R² is halo, C₁₋₆alkyl, C₁₋₆alkenyl,C₁₋₆alkyloxy, trihalomethoxy or hydroxy C₁₋₆alkyloxy.
 6. The method ofclaim 1 wherein in Formula (I) R⁶ is hydrogen, hydroxy, halo C₁₋₆alkyl,hydroxy C₁₋₆alkyl cyano C₁₋₄alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl,imidazolyl, or a radical of formula —NR¹¹R¹² wherien R¹¹ is hydrogen orC₁₋₁₂alkyl and R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy,C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, hydroxy or a radical of formula-ALK²—OR¹³wherein R is hydrogen or C¹⁻⁶ alkyl.
 7. The method of claim 1 whereinthe compound is(+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone;or a pharmaceutically acceptable acid additional salt thereof.